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CCN/WISP (cellular communication network factors, or Wnt-inducted secreted proteins) family of proteins consists of six extracellular matrix (ECM)-associated proteins that regulate development, cell adhesion and proliferation, ECM remodeling, inflammation, and tumorigenesis. In the last two decades, metabolic regulation by these matricellular proteins has been studied extensively, several excellent reviews have covered the roles of CCN1, -2 and − 5. In this brief review, we will focus on those lesser-known members and more recent discoveries, together with other recent articles presenting a more complete picture of the current state of knowledge. We have found that CCN2, -4, and − 5 promote pancreatic islet function, while CCN3 plays a unique and negative role. CCN3 and − 4 are pro-adiposity leading to insulin resistance, but CCN5 and − 6 are anti-adiposity. While CCN2 and − 4 promote tissue fibrosis and inflammation, all other four members are clearly anti-fibrotic. As for cellular signaling, they are known to interact with integrins, other cell membrane proteins and ECM thereby regulate Akt/protein kinase B, myocardin-related transcription factor (MRTF), and focal adhesion kinase. Yet, a cohesive mechanism of action to comprehensively explain those major functions is still lacking. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Central South University is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Persistent acinar to ductal metaplasia (ADM) is a recently recognized precursor of pancreatic ductal adenocarcinoma (PDAC). Here we show that the ADM area of human pancreas tissue adjacent to PDAC expresses significantly higher levels of regenerating protein 3A (REG3A). Exogenous REG3A and its mouse homolog REG3B induce ADM in the 3D culture of primary human and murine acinar cells, respectively. Both Reg3b transgenic mice and REG3B-treated mice with caerulein-induced pancreatitis develop and sustain ADM. Two out of five Reg3b transgenic mice with caerulein-induced pancreatitis show progression from ADM to pancreatic intraepithelial neoplasia (PanIN). Both in vitro and in vivo ADM models demonstrate activation of the RAS-RAF-MEK-ERK signaling pathway. Exostosin-like glycosyltransferase 3 (EXTL3) functions as the receptor for REG3B and mediates the activation of downstream signaling proteins. Our data indicates that REG3A/REG3B promotes persistent ADM through binding to EXTL3 and activating the RAS-RAF-MEK-ERK signaling pathway. Targeting REG3A/REG3B, its receptor EXTL3, or other downstream molecules could interrupt the ADM process and prevent early PDAC carcinogenesis. Using several human and murine models, Zhang et al discover a role for the REG3A/REG3B proteins in acinar to ductal metaplasia (ADM), a precursor of pancreatic ductal adenocarcinoma (PDAC). They find that REG3B induces ADM through RAS-RAF-MEK-ERK signaling and identify EXTL3 as a REG3B receptor, providing new insights into PDAC development. [ABSTRACT FROM AUTHOR]

Objective: To investigate apoptotic effects of berberine, a significant alkaloids component existing in Rhizoma coptidis, and its possible acting mechanism in insulinoma cells. Methods: Different concentrations of berberine were used to treat mouse insulinoma (MIN6) cells for various period of time. The viability and apoptosis of the cells were analyzed using methylthiazolyldiphenvl-tetrazolium bromide assay, flow cytometry and enzyme-linked immuno sorbent assay. Changes in the relating pro- and anti-apoptosis proteins were detected by western-blotting. Results: The half-maximal inhibitory concentration (IC50) of berberine was 5.7 μmol/L on MIN6 cells viability for 16 h. Berberine caused a 20% reduction (P<0.05) in cell number after only 4-h incubation; which reached 50% after 24 h (P<0.01). Berberine treatment for 16 h significantly increased the level of DNA fragmentation. The flow cytometry showed the apoptotic rate increased 2.9- and 4.6-fold after treating with berberine (5 μmol/L) for 8 and 16 h, while 3- and 8.7-fold after 10 μmol/L treatment for 8 and 16 h (P<0.01). Berberine treatment dramatically elevated the expression ratio of Bax to Bcl-2. Meanwhile, berberine notably increased the apoptosis-inducing factors and cytochrome C transforming from the mitochondria to the cytoplasm. Apoptotic protease-activating factor 1 (Apaf-1) was subsequently activated after cytochrome C release. Furthermore, caspase-3 and poly adenosine diphosphate-ribose polymerase were also activated to trigger apoptosis cascade. Conclusion: High concentration (5 and 10 μmol/L) of berberine could induce the apoptosis of MIN6 cells through cytochrome C/Apaf-1/caspase-3 and apoptosis inducing factor (AIF) pathway. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Zhejiang University: Science B is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Purpose: In view of the numerous clinical observations and laboratory studies that suggest a critical role for the spleen in immune thrombocytopenia (ITP) pathophysiology, we aimed to characterize Th1-associated chemokine receptors CXCR3 and CCR5 and Th2-associated chemokine receptor CCR3 in spleens of ITP patients and assess the significance of their differential expression in the clinical setting. Methods: The histopathology of spleens was observed using hematoxylin-eosin staining (HE), and the positive rate of CXCR3, CCR5 and CCR3 expression in spleens of 24 ITP patients and 12 patients with traumatic splenic rupture as normal controls was detected by immunohistochemistry using the SP method. CXCR3, CCR5 and CCR3 protein expression was analyzed by Western blot and mRNA levels were investigated by real-time polymerase chain reaction (RT-PCR). Results: Reactive hyperplasia could be seen in follicles of the white pulp, the germinal central zone was enlarged and the marginal zone was thickened, the central arteries were thickened and fibrotic, and the density of the capillary vessel was increased in ITP patients. ITP group displayed a higher rate of expression of Th1-associated chemokine receptors CXCR3 and CCR5 (83.3 % vs. 75 %, 100 % vs. 83.3 %) but lower rate of expression of Th2-associated chemokine receptor CCR3 (50 % vs. 66.7 %) compared with the controls ( P < 0.05, respectively). Western blot analysis revealed that CXCR3 and CCR5 protein expression was significantly increased in ITP patients while CCR3 was significantly reduced ( P < 0.05, respectively). Meanwhile, ITP patients displayed increased mRNA levels of CXCR3 and CCR5 but decreased gene expression of CCR3 ( P < 0.05, respectively). Conclusion: The data suggested that the abnormal expression of Th1/Th2 chemokine receptors may participate in splenic immune disorder in patients with ITP. Using corresponding inhibitors may inhibit Th1-dominant expression and mitigate the progress of the disease. [ABSTRACT FROM AUTHOR]

Overall outcome of those patients with non-small cell lung cancer (NSCLC) remains poor. Recently, several studies demonstrated that cyclin-dependent kinase-5 (CDK5) activity with its specific activator protein p35 was important for spontaneous metastasis in various types of carcinomas. Our objective was to explore the expression of CDK5 and its prognostic indicator in patients with NSCLC. Immunofluorescent staining was used to detect the expression of CDK5/p35 in the lung tissue of 95 patients with NSCLC and 20 patients with benign pulmonary disease. The correlation between the expression of CDK5/p35 and clinicopathologic features of patients with NSCLC was investigated. The 5-year overall survival of patients with tumors expressing different levels of CDK5/p35 was evaluated by the Kaplan-Meier method. Positive expressions of CDK5/p35 were detected in the tumor cells in 66 samples (69.5%) of the 95 patients with NSCLC. Although no remarkable correlation between CDK5/p35 expression and age at the time of surgery, gender, and histopathologic type, there were significant differences between CDK5/p35 expression and degree of differentiation, pathological stage and lymph node metastasis in patients with NSCLC. In addition, we demonstrated that median survival for patients with and without CDK5/p35 expression was 24 and 58 months, respectively, and 5-year overall survival rate 25.8 and 48.3%, respectively ( P < 0.05). Patients with lung cancer with a positive CDK5/p35 expression had a poorer prognosis than those with a negative CDK5/p35 expression. Based on our results, CDK5/p35 may represent a biomarker for prognosis in patients with NSCLC. [ABSTRACT FROM AUTHOR]

Activation of the sympathetic nervous system is a compensatory mechanism which initially provides support for the circulation in the face of a falling cardiac output. It has been recognized for some time that chronic elevation of sympathetic outflow with the consequent increase in plasma norepinephrine, is counterproductive to improving cardiac function. Indeed, therapeutic targeting to block excessive sympathetic activation in heart failure is becoming a more accepted modality. The mechanism(s) by which sympathetic excitation occurs in the heart failure state are not completely understood. Components of abnormal cardiovascular reflex regulation most likely contribute to this sympatho-excitation. However, central mechanisms which relate to the elaboration of angiotensin II (Ang II) and nitric oxide (NO) may also play an important role. Ang II has been shown to be a sympatho-excitatory peptide in the central nervous system while NO is sympatho-inhibitory. Recent studies have demonstrated that blockade of Ang II receptors of the AT1 subtype augments arterial baroreflex control of sympathetic nerve activity in the heart failure state, thereby predisposing to a reduction in sympathetic tone. Ang II and NO interact to regulate sympathetic outflow. Blockade of NO production in normal conscious rabbits was only capable of increasing sympathetic outflow when accompanied by a background infusion of Ang II. Conversely, providing a source of NO to rabbits with heart failure reduced sympathetic nerve activity when accompanied by blockade of AT1 receptors. Chronic heart failure is also associated with a decrease in NO synthesis in the brain as indicated by a reduction in the mRNA for the neuronal isoform (nNOS). Chronic blockade of Ang II receptors can up regulate nNOS expression. In addition, exercise training of rabbits with developing heart failure has been shown to reduce sympathetic tone, decrease plasma Ang II, improve arterial baroreflex function and increase nNOS expression in the central nervous system. This review summarizes a large number of studies which have concentrated on the mechanisms of sympatho-excitation in heart failure. It now seems clear that one mechanism which is important in regulating sympathetic outflow in this disease state depends upon a central interaction between Ang II and NO at the cellular and nuclear levels. [ABSTRACT FROM AUTHOR]